Complex interactions between lead and essential elements, primarily calcium, iron, zinc copper, and have been reported in clinical and experimental studies. The mechanisms and toxicological significance of these interactions are not clearly understood. Out objective is to extend our previous finding by conducting a series of experiments at the whole animal, cellular, and subcellular level to evaluate the effects of lead intoxication on the cellular homeostasis and essential functions of calcium and iron. Together these experiments will test the general hypothesis that lead toxicity is expressed via a perturbation of the cellular homeostasis and function of essential elements. The specific aims of this proposal are to: In Vivo 1. evaluate the effect of lead intoxication on the concentration of essential elements in selected microscopic regions of kidney, brain, aorta, ileum, and liver of rats. In Vitro (Calcium) 2. compare the subcellular localization of Pb and Ca and to determine the subcellular site(s) of lead-induced calcium accumulation in cultured hepatocytes. 3. determine the route(s) by which 203Pb enters cells and to compare the roles and relative importance of passive diffusion, fluid-phase endocytosis, and carrier-mediated transport (calcium gates) in the entry of Pb2+ into cells. 4. evaluate the effect of lead on the regulation of cytosolic free [Ca2+] in microsomes, mitochondria, and permeabilized rat hepatocytes. 5. evaluate the effect of lead intoxication on calmodulin- and calcium- mediated cell functions located in selected subcellular calcium-domains of cultures rat hepatocytes. In Vitro (Iron) 6. develop a kinetic model for the steady-state cellular homeostasis of 59Fe in cultured hepatocytes. 7. evaluate the effect of lead intoxication on the cellular homeostasis of 59Fe in cultured rat hepatocytes. 8. correlate the lead induced changes in iron homeostasis with iron-mediated cell function and heme biosynthesis in cultured rat hepatocytes.